Pump as a pressure source for supercritical fluid chromatography

ABSTRACT

The invention is a device and method in a high-pressure chromatography system, such as a supercritical fluid chromatography (SFC) system, that uses a pump as a pressure source for precision pumping of a compressible fluid. The preferred exemplary embodiment comprises a pressure regulation assembly installed downstream from a compressible fluid pump but prior to combining the compressible flow with a relatively incompressible modifier flow stream. The present invention allows the replacement of an high-grade SFC pump in the compressible fluid flow stream with an inexpensive and imprecise pump. The imprecise pump becomes capable of moving the compressible fluid flow stream in a precise flow rate and pattern. The assembly dampens the damaging effects of an imprecise pump, such as large pressure oscillations caused by flow ripples and noisy pressure signals that do not meet precise SFC pumping requirements.

This is a Division of application Ser. No. 10/117,984, filed Apr. 05,2002, now U.S. Pat. No. 6,648,609. The invention relates to a device andmethod for using a pump as a pressure source, instead of a flow source,in a high-pressure chromatography system, such as supercritical fluidchromatography.

FIELD OF THE INVENTION

The invention relates to a device and method for using a pump as apressure source, instead of a flow source, in a high-pressurechromatography system, such as supercritical fluid chromatography.

BACKGROUND OF THE INVENTION

An alternative separation technology called supercritical fluidchromatography (SFC) has advanced over the past decade. SFC uses highlycompressible mobile phases, which typically employ carbon dioxide (CO2)as a principle component. In addition to CO2, the mobile phasefrequently contains an organic solvent modifier, which adjusts thepolarity of the mobile phase for optimum chromatographic performance.Since different components of a sample may require different levels oforganic modifier to elute rapidly, a common technique is to continuouslyvary the mobile phase composition by linearly increasing the organicmodifier content. This technique is called gradient elution.

SFC has been proven to have superior speed and resolving power comparedto traditional HPLC for analytical applications. This results from thedramatically improved diffusion rates of solutes in SFC mobile phasescompared to HPLC mobile phases. Separations have been accomplished asmuch as an order of magnitude faster using SFC instruments compared toHPLC instruments using the same chromatographic column. A key factor tooptimizing SFC separations is the ability to independently control flow,density and composition of the mobile phase over the course of theseparation. SFC instruments used with gradient elution alsoreequillibrate much more rapidly than corresponding HPLC systems. As aresult, they are ready for processing the next sample after a shorterperiod of time. A common gradient range for gradient SFC methods mightoccur in the range of 2% to 60% composition of the organic modifier.

It is worth noting that SFC instruments, while designed to operate inregions of temperature and pressure above the critical point of CO2, aretypically not restricted from operation well below the critical point.In this lower region, especially when organic modifiers are used,chromatographic behavior remains superior to traditional HPLC and oftencannot be distinguished from true supercritical operation.

A second analytical purification technique similar to SFC issupercritical fluid extraction (SFE). Generally, in this technique, thegoal is to separate one or more components of interest from a solidmatrix. SFE is a bulk separation technique, which does not necessarilyattempt to separate individually the components, extracted from thesolid matrix. Typically, a secondary chromatographic step is required todetermine individual components. Nevertheless, SFE shares the commongoal with prep SFC of collecting and recovering dissolved components ofinterest from supercritical flow stream. As a result, a collectiondevice suitable for preparative SFC should also be suitable for SFEtechniques.

Packed column SFC uses multiple, high pressure, reciprocating pumps,operated as flow sources, and independent control of system pressurethrough the use of electronic back pressure regulators. Such aconfiguration allows accurate reproducible composition programming,while retaining flow, pressure, and temperature control. Reciprocatingpumps are generally used in supercritical fluid chromatography systemsthat use a packed chromatography column for elution of sample solutes.Reciprocating pumps can deliver an unlimited volume of mobile phase withcontinuous flow, typically pumping two separate flow streams of acompressible supercritical fluid and incompressible modifier fluid thatare combined downstream of the pumping stages to form the mobile phase.Reciprocating pumps for SFC can be modified to have gradient elutionoperational capabilities.

A great deal of subtlety is required to pump fluids in SFC. Not anyreciprocating pump can be used with a pump head chiller to make an SFCpump. While most HPLC pumps can be set to compensate for thecompressibility, compensation is too small to deal with the fluids mostoften used in SFC. To attempt to minimize the compressibility rangerequired, the pump is usually chilled to insure the fluid is a liquid,far from its critical temperature. Chilled fluids are dense but arestill much more compressible than the normal liquids used in HPLC. Tocontrol flow accurately, the pump must have a larger than expectedcompressibility compensation range. Further, since the compressibilitychanges with pressure and temperature, the pump must be capable ofdynamically changing compressibility compensation. Inadequatecompensation results in errors in both the flow rate and the compositionof modified fluids.

Without correct compressibility compensation, the pump either under- orover-compresses the fluid causing characteristic ripples in flow andpressure. Either under- or over-compression results in periodicvariation in both pressure and flow with the characteristic frequency ofthe pump (ml/min divided by pump stroke volume in ml). The result isnoisy baselines and irreproducibility. To compensate for this, the moreexpensive and better liquid chromatography pumps have compressibilityadjustments to account for differences in fluid characteristics.

SFC systems in the prior art have used modified HPLC high-pressure pumpsoperated as a flow source. One pump delivered compressible fluids, whilethe other was usually used to pump modifiers. A mechanical back pressureregulator controlled downstream pressure. The pumps used a singlecompressibility compensation, regardless of the fluids used. Thecompressible fluid and the pump head were cooled near freezing. Thedelivery of carbon dioxide varied with pressure and flow rate. Thesecond pump delivered accurate flows of modifier regardless of pressureand flow. At different pressures and flows, the combined pumps delivereddifferent compositions although the instrument setpoints remainedconstant. Pumping compressible fluids, such as CO2, at high pressures inSFC systems while accurately controlling the flow, is much moredifficult than that for a liquid chromatography system. SFC systems usetwo pumps to deliver fluids to the mobile phase flow stream, and eachpump usually adds pressure and flow ripples and variances that causebaseline noise. The two pumps also operate at different frequencies,different flow rates, and require separate compressibilitycompensations, further adding to the complexity of flow operations.

Methods in the prior art calculate ideal compressibility based onmeasured temperature and pressure using a sophisticated equation ofstate. The method then uses dithering around the setpoint to see if asuperior empirical value can be found. This approach is described inU.S. Pat. No. 5,108,264, Method and Apparatus for Real Time Compensationof Fluid Compressibility in High Pressure Reciprocating Pumps, and U.S.Pat. No. 4,883,409, Pumping Apparatus for Delivering Liquid at HighPressure. Other prior art methods move the pump head until the pressurein the refilling cylinder is nearly the same as the pressure in thedelivering pump head. One method in U.S. Pat. No. 5,108,264 Method andApparatus for Real Time Compensation of Fluid Compressibility in HighPressure Reciprocating Pumps, adjusts the pumping speed of areciprocating pump by delivering the pumping fluid at high pressure anddesired flow rate to overcome flow fluctuations. These are completelyempirical forms of compressibility compensation. The prior art methodsrequire control of the fluid temperature and are somewhat limited sincethey does not completely compensate for the compressibility. Thecompensation stops several hundred psi from the column inlet pressure.

In SFC, it is common to use very long columns with large pressure dropsto generate very high efficiency compared to HPLC. The use of longcolumns resulted from a change in control philosophy. Earlier in SFCtechnology, the pump was used as the pressure controller. the columnoutlet pressure was not controlled. Long columns produced large pressuredrops, and at modest inlet pressures, the outlet pressure could drop tothe point where several sub-critical phases could exist. Theco-existence of several phases destroys chromatographic separations andefficiency. Controlling the column outlet pressure, the pump becomes aflow source, not a pressure source. Consequently, the point in thesystem with the worst solvent strength becomes the control point. Allother positions in the system have greater solvent strength. Bycontrolling this point, problems associated with phase separations orsolubility problems at uncontrolled outlet pressures are eliminated.

The compressibility of the pumping fluid directly effects volumetricflow rate and mass flow rate. These effects are much more noticeablewhen using compressible fluids such as carbon dioxide in SFC rather thanfluids in liquid chromatography. The assumption of a constantcompressibility leads to optimal minimization of fluid fluctuation atonly one point of the pressure/temperature characteristic, but at otherpressures and temperatures, flow fluctuations occur in the system.

The flow rate should be kept as constant as possible through theseparation column. If the flow rate fluctuates, variations in theretention time of the injected sample would occur such that the areas ofthe chromatographic peaks produced by a detector connected to the outletof the column would vary. Since the peak areas are representative forthe concentration of the chromatographically separated sample substance,fluctuations in the flow rate would impair the accuracy and thereproducibility of quantitative measurements. At high pressures,compressibility of solvents is very noticeable and failure to accountfor compressibility causes technical errors in analyses and separationin SFC.

The type of pump control philosophy in an SFC system affects resolutionin pressure programming. A pressure control pump with a fixed restrictorresults in broadened peaks and higher background noise through a packedcolumn. Efficiency degrades as pressure increases. A flow control pumpwith a back-pressure regulator has better resolution results through apacked column and steady background. Efficiency remains constant withincreasing pressure. With independent flow control, the chromatographiclinear velocity is dictated by the pump, and remains near optimum,throughout a run. The elution strength is controlled separately, using aback-pressure regulator. With pressure controlled pumps, a fixedrestrictor passively limits flow. The linear velocity increasesexcessively during a run, thereby degrading the chromatography.

Therefore, a need exists for a system that uses a pump as a pressuresource in SFC without degrading the chromatography results.

SUMMARY

The exemplary embodiment is useful in a high-pressure chromatographysystem, such as a supercritical fluid chromatography (SFC) system, forusing a pump as a pressure source for precision pumping of acompressible fluid. The preferred exemplary embodiment comprises apressure regulation assembly installed downstream from a compressiblefluid pump but prior to combining the compressible flow with arelatively incompressible modifier flow stream that allows thereplacement of an high-grade SFC pump in the compressible fluid flowstream with an inexpensive and imprecise pump. The imprecise pumpbecomes capable of moving the compressible fluid flow stream in aprecise flow rate and pattern. The assembly dampens the damaging effectsof an imprecise pump, such as large pressure oscillations caused by flowripples and noisy pressure signals that do not meet precise SFC pumpingrequirements.

The invention regulates the outlet pressure from a pump using a systemof pressure regulators and a restriction in the flow stream. To regulateoutlet pressure directly downstream of a pump, a forward-pressureregulator (FPR) is installed in the flow line. Downstream of theforward-pressure regulator the flow is restricted with a precisionorifice. The orifice can be any precision orifice, such as a jewelhaving a laser-drilled hole or precision tubing. Downstream of theorifice is a back-pressure regulator (BPR). The series of anFPR-orifice-BPR is designed to control the pressure drop across theorifice, which dampens out oscillation from noisy pressure signalscaused by large ripples in the flow leaving the pump. An additionalembodiment uses a differential pressure transducer around the orificewith a servo control system to further regulate the change in pressureacross the orifice. The combination allows the replacement of anexpensive, SFC-grade pump having compressibility compensation with aninexpensive, imprecise pump such as an air-driven pump.

The system can be multiplexed in parallel flow streams, thereby creatingsignificantly greater volumetric capacity in SFC and a greater number ofinexpensive compressible fluid flow channels. The parallel streams canall draw from a single source of compressible fluid, thereby reducingthe costs of additional pumps. Some alternatives to the multiplexedsystem uses the single compressible fluid pump to raise pressure in theflow line from the compressible fluid source combined with additionalsecond stage booster pumps in each individual SFC flow stream. Anothersystem replaces multiple modifier solvent pumps for each channel with asingle, multi-piston pump having outlets for each individual channel.

BRIEF DESCRIPTION OF THE DRAWINGS

For a better understanding of the nature of the present invention,reference is had to the following figures and detailed description,wherein like elements are accorded like reference numerals, and wherein:

FIG. 1 is a flow diagram of an supercritical fluid chromatographysystem.

FIG. 2 is a schematic of a compressible fluid flow stream with thepreferred embodiment.

FIG. 3 is a schematic of a compressible fluid flow stream with analternative embodiment.

FIG. 4 is a schematic of a multiplexed compressible fluid flow streamusing the invention in parallel with multiple pumps.

FIG. 5 is a schematic of a multiplexed compressible fluid flow streamusing the invention in parallel with a single pump.

FIG. 6 is a schematic of a multiplexed compressible fluid flow streamusing the invention in parallel with two pumps.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

There is described herein a preferred embodiment of the presentinvention for a device and method in a high-pressure chromatographysystem, such as supercritical fluid chromatography (SFC), that uses apump as a pressure source for precision pumping of a compressible fluid.As further described herein, the preferred exemplary embodimentcomprises a pressure regulation assembly installed downstream from acompressible fluid pump but prior to combining the compressible flowwith a relatively incompressible flow stream. The present inventionprovides for the replacement of an expensive SFC-grade pump forcompressible fluids having dynamic compressibility compensation, with aless-expensive and imprecise pump to move a compressible fluid flowstream in a precise flow rate and pressure signal. The assembly dampensthe damaging effects of a low-grade pump, such as large pressure andflow oscillations caused by flow ripples and noisy pressure signals thatdo not meet precise SFC pumping requirements.

Components of an SFC system 10 are illustrated in the schematic ofFIG. 1. The system 10 comprises two independent flow streams 12, 14combining to form the mobile phase flow stream. In a typical SFC pumpingassembly, a compressible fluid, such as carbon dioxide (CO2), is pumpedunder pressure to use as a supercritical solvating component of a mobilephase flow stream. Tank 18 supplies CO2 under pressure that is cooled bychiller 20. Due to precise pumping requirements, SFC systems commonlyuse an SFC-grade reciprocating piston pump havingdynamic-compressibility compensation.

A second independent flow stream in the SFC system provides modifiersolvent, which is typically methanol but can be a number of equivalentsolvents suitable for use in SFC. Modifier is supplied from a supplytank 24 feeding a second high-grade pump for relatively incompressiblefluids 26. Flow is combined into one mobile phase flow stream prior toentering mixing column 30. The combined mobile phase is pumped at acontrolled mass-flow rate from the mixing column 30 through transfertubing to a fixed-loop injector 32 where a sample is injected into theflow stream.

The flow stream, containing sample solutes, then enters a chromatographycolumn 34. Column 34 contains stationary phase that elutes a sample intoits individual constituents for identification and analysis. Temperatureof the column 34 is controlled by an oven 36. The elution mixtureleaving column 34 passes from the column outlet into detector 40.Detector 40 can vary depending upon the application, but commondetectors are ultraviolet, flame ionization (with an injector- orpost-column split), or GC/MS. After analysis through the detector 40,the mobile phase flow stream passes through a back-pressure regulator(BPR) 42, which leads to a downstream sample fraction collection system44.

For precision SFC pumping, pump 22 must have some type ofcompressibility compensation, otherwise pressure ripples and flowfluctuations will result in noisy baselines and irreproducibility offlow rates and pressures. Compressibility compensation accounts forunder or over-compensation in the piston and differences in fluidcompressibilities. High-pressure SFC pumps used as flow sources have anextended compressibility range and the ability to dynamically change thecompression compensation. The compressibility of the pumping fluiddirectly effects volumetric flow rate and mass flow rate. These effectsare much more noticeable when using compressible fluids, such as CO2, inSFC systems than fluids in liquid chromatography. The assumption of aconstant compressibility leads to optimal minimization of fluidfluctuation at only one point the pressure/temperature characteristic,but at other pressures and temperatures, flow fluctuations occur in thesystem. If the mobile phase flow rate is not kept as constant aspossible through the column, variation in the retention time of theinjected sample would occur such that the areas of the chromatographicpeaks measured by a detector connected to the outlet of the columnswould vary. Since the peak areas are representative of the concentrationof the separated sample solutes, fluctuations in the flow rate wouldimpair the accuracy and the reproducibility of quantitativemeasurements. At high pressures, compressibility of solvents is verynoticeable and failure to account for compressibility causes technicalerrors in analyses and separation in SFC.

FIG. 2 is a schematic of an SFC system with the device of the preferredexemplary embodiment installed on flow line 14, containing compressiblesupercritical fluid. After pump source 52, a forward pressure regulator(FPR) 46 is installed on flow line 14. After the FPR 46, a type of fixedrestrictor 48 is followed by a back-pressure regulator (BPR) 50. The FPR46 installed directly downstream of pump source 52 dampens outoscillation from noisy pressure signals caused by large ripples in theflow leaving pump source 52. This effect provides near-constant outletpressure from pump source 52. Downstream of the FPR is tubing 54connected on opposite sides of a fixed restrictor 48. In the preferredembodiment, the fixed restrictor 48 is a precision orifice. The orificecan be any precision orifice, such as a jewel having a laser-drilledhole or precision tubing.

Any types of FPRs and BPRs capable of use in SFC systems may beimplemented for the present invention. Pressure regulators 46, 50 may bemechanically, electro-mechanically, or thermally controlled. Pressureregulators 46, 50 should have low dead volumes if peak collection is animportant result. Some older generation pressure regulators 46, 50 havedead volumes as high as 5 ml and therefore should be avoided. Pressureregulators may also be heated to prevent the formation of solidparticles of the mobile phase from forming.

The configuration of a precision orifice 48 between an FPR 46 and BPR 50is designed to control the pressure drop ΔP across the orifice 48.Controlling ΔP will control the flow of compressible fluid in thesystem. The flow past the orifice 48 should remain as close to constanttemperature as possible. Changing the size of the orifice 48 changes theflowrate range. The invention can operate with some drop in pressure ifthere is little temperature change. If there is a drop in ΔP in additionto cooling across orifice 48, the positive effects of flow control beginto degrade. The orifice is set to create a restriction which limits themass flow rate. With fixed restrictors, SFC must achieve operatingpressures by varying the flow rates. The size of the static orifice canbe changed to create discrete pressure levels at flow rate that providethe same integrated mass of expanded mobile phase at each pressuresetting.

The preferred embodiment operates most efficiently for small ΔP acrossthe single orifice 48, sending flow from repeated injections of similarsamples through a single column 34 while knowing the gradient of flow.To assist in maintaining the constant flow stream, the pressure source52 pumps flow at a pressure higher than any pressure required throughoutthe system. For example, CO2 flow rates may range from 37.5 ml/minute to25 ml/minute at pressures up to 400 bar. As one skilled in the art willunderstand, alternative embodiments of the invention can operate underconditions that can vary significantly from exemplary embodiments. Forexample, a variable orifice can change ΔP and the flow rate according toadjustments made by a control system.

According to the present invention, an SFC pump is converted from a flowsource into using the pump as a pressure source while continuing tocontrol the flow rate. The preferred embodiment allows for constant massflow of compressible fluids and even provides for constant mass flow inthe presence of rising outlet pressure. As the pump 52 sends mobilephase through the column and more fluid from both flow streams arepumped together, and pressure rises in the flow stream independent ofthe fact that less percentage of CO2 is being pumped. After the CO2leaves the BPR 50, the pressure drops to an undefined value, which is inthe column inlet pressure. The column inlet pressure has no effect onflow control of the present invention unless the column pressure becomestoo high through a system malfunction or inadvertent operator mistake.Pump 52 is also operated at a pressure higher than any downstreampressure requirements. With these operating conditions, the describedsystem is useful in a system built for analytical or semi-preparatory topreparatory supercritical fluid chromatography but may also be used inHPLC or supercritical fluid extraction systems.

By utilizing the series of pressure regulators 46, 50 with a precisionorifice 48 placed after a pressure source 52 in the compressible fluidflow stream 14, a high cost SFC-grade pump can be replaced with aninexpensive, lower-grade pump. An example of a replacement for pump 22is a piston-drive pneumatic pump 52. An air driven pump can be modifiedfor use in an SFC system to deliver compressible fluids at extremelyhigh pressures, such as 10,000 psi. A pneumatic pump is not typicallyused in SFC systems because of significant problems with imprecise flowand pressure parameters, such as pressure ripples producing noisypressure signals. The present invention provides precise flow bydampening out a noisy pressure signal and uneven flow so that apneumatic pump functions as well as an SFC-grade reciprocating pump.

An alternative embodiment to the present invention is illustrated inFIG. 3. The schematic of an SFC system shows a source of compressiblefluid 18 feeding compressible fluid pump 52. Flow line 14 feeds an FPR46, a fixed restrictor 48, following by a BPR 50. FPR 46 is installeddirectly downstream of pressure source 52 and dampens out oscillationfrom noisy pressure signals caused by large ripples in the flow leavingpump 52, thereby providing nearly constant outlet pressure. In thealternative embodiment, the fixed restrictor 48 is a precision orifice.The orifice can be any precision orifice, such as a jewel having alaser-drilled hole or precision tubing. A differential pressuretransducer 58 can be installed on flow lines 54 and 56 aroundrestrictive orifice 48 to control ΔP across the orifice 48. Thedifferential transducer 58 is being used as a mass flow transducer andemploys a servo control system for performing a servo algorithm tocontrol the transducer 58 in accordance with the requirements of thepresent invention.

In an additional alternative embodiment, illustrated in FIG. 4, flowchannels of compressible fluid flow streams are multiplexed in parallel,thereby creating significantly greater volumetric capacity in SFCsystems. Pumps 52 may draw from a single source of compressible sourcefluid 18, such as CO2. Flow control is gained from pressure flow out ofpumps 52 operating with duplicated series of a restrictive orifice 48between FPR 46 and BPR 50, according to the present invention. Themultiplexed system is illustrated having a differential transducer 58installed around restrictive orifice 48, however as described in thepreferred embodiment, flow control of a pressure source may be practicedwithout transducer 58. Higher cost SFC-grade pumps are replaced withlow-grade, imprecise compressible fluid pumps 52, thereby providing acost-effective plurality of channels of compressible flow streams.

FIG. 4 illustrates an individual modifier pump 26 fed by a common supplytank 24 for each modifier flow stream 12 that feeds into thecompressible fluid flow stream prior to entering the mixing column 30 ineach of the multiplexed pumping systems. An alternative embodiment tothis design is to use a single modifier pump 26, such as a multi-pistonpump, that has multiple flow outlets that can feed multiple channels. Amulti-piston pump draws modifier from tank 24 and distributes flow toeach modifier flow stream 12 from the single pump. In the exemplaryembodiment in FIG. 4, a single four port multi-piston pump couldsubstitute for the four modifier pumps 26 for the multiplexed system.

In an additional exemplary embodiment, illustrated in FIG. 5, thecompressible fluid flow stream of an SFC system is multiplexed inparallel from single pump 52. For this application, outlet pressure ofpump 52 is kept much higher than pressure used in a single flow channel.Flow is distributed to each parallel channel through any pressuredistribution control device compatible with the compressible sourcefluid and the high-pressures necessary for SFC systems. Flow control isgained from pressure flow operating with duplicated series of arestrictive orifice 48 between FPR 46 and BPR 50 for each parallelchannel. The multiplexed system is illustrated having a differentialtransducer 58 installed around restrictive orifice 48, however asdescribed in the preferred embodiment, flow control of a pressure sourcemay be practiced without transducer 58. A higher cost SFC-grade pump isreplaced with low-grade, imprecise compressible fluid pump 52, therebyproviding a cost-effective plurality of channels of compressible flowstreams.

Reference is made to FIG. 6, illustrating another embodiment of thepresent invention. In this embodiment, compressible fluid flows to therestrictive orifice 48 from two pumps. The first is a compressible fluidpump 52 that is fed directly from the compressible fluid supply tank 18.This pump 52 raises flow pressure to a consistent level very near thecritical point. For example, pressure is raised by pump 52 between 200and 1200 psi in the first stage. Pump 52 is then followed by a secondstage booster pump 60 for each channel on the compressible fluid flowstream. The booster pump 60 raises pressure in the individual flow linesleading to orifice 48. In an example, pressure in line 14 from pump 60ranges from 1200 to 6000 psi.

The present invention is well suited for use in chromatography systemsoperating in the supercritical, or near supercritical, ranges of flowstream components. However, as one skilled in the art will recognize,the invention may be used in any system where it is necessary to obtainsteady flow of liquid at high pressures with high degrees of accuracy ofpressure and flow using an imprecise pressure source. Other applicationsmay include supercritical fluid extraction systems or HPLC whereseparation and/or collection of sample contents into a high-pressureflow stream occurs.

Because many varying and different embodiments may be made within thescope of the inventive concept herein taught, and because manymodifications may be made in the embodiments herein detailed inaccordance with the descriptive requirements of the law, it is to beunderstood that the details herein are to be interpreted as illustrativeand not in a limiting sense.

1. A method for using a pump as pressure source in a flow streamcontaining a highly compressed gas, compressible liquid, orsupercritical fluid, comprising the steps of: restricting the flowstream at a point downstream of the pump with a restrictor; regulatingoutlet pressure of the pump at a point upstream of the restrictor;regulating back pressure in the flow stream at a point downstream of therestictor; and combining the flow stream, at a point downstream of theregulating back pressure, with a second flow stream from a relativelyincompressible fluid, wherein the regulating back pressure in the flowstream comprises regulating the back pressure in the flow stream with aback-pressure regulator at a point prior to said combining said secondflow stream with the flow stream.
 2. The method of claim 1, wherein thestep of restricting the flow stream comprises applying a fixedrestriction in the flow stream at a point downstream of the pump with anorifice.
 3. The method of claim 1, wherein the step of regulating theoutlet pressure of the pump comprises regulating the forward pressure ofthe flow stream at a point upstream of the restrictor with aforward-pressure regulator.
 4. The method of claim 1, wherein the stepof restricting the flow steam further comprises controlling a pressuredrop across the restrictor.
 5. The method of claim 1, wherein the stepof restricting the flow stream, the step of regulating outlet pressure,and the step of regulating back pressure are applied to a plurality offlow streams manifolded from the outlet of the pump.
 6. The method ofclaim 5, further comprising the steps of: pumping a flow stream in eachof the plurality of flow streams using a booster pump connected intoeach of the plurality of flow streams; and controlling a pressure dropacross each restrictor in each of the plurality of flow streams.
 7. Themethod of claim 5, further comprising the steps of: combining a secondflow stream of a relatively incompressible fluid into each of theplurality of flow streams, downstream of said regulating back pressure,using a single multi-piston pump.
 8. The method of claim 1, wherein thestep of restricting further comprises controlling a pressure drop acrosssaid restrictor using a differential pressure transducer.
 9. A methodfor using a pump as pressure source in a flow stream containing a highlycompressed gas, compressible liquid, or supercritical fluid, comprisingthe steps of: regulating outlet pressure of the pump with a forwardpressure regulator located downstream of the pump; restricting the flowstream with a fixed orifice located downstream of the forward pressureregulator; regulating pressure in the flow stream with a back pressureregulator located downstream of the fixed orifice, and combining saidflow stream, at a point downstream of the regulating back pressure, witha second flow stream from a relatively incompressible fluid, wherein theregulating pressure in the flow stream comprises regulating the backpressure in the flow stream with the back pressure regulator at a pointprior to said combining said flow stream with the second flow stream,and wherein the regulating pressure controls a pressure drop across thefixed orifice.
 10. The method of claim 9, wherein the steps ofrestricting the flow steam further comprises controlling a pressure dropacross the restrictor with a differential pressure transducer.
 11. Themethod of claim 9, wherein the step of restricting the flow stream, thestep of regulating outlet pressure, and the step of regulating pressurein the flow stream with the back pressure regulator are applied to aplurality of flow streams manifolded from the outlet of the pump.
 12. Amethod for using a pump as a pressure source in a flow stream containinga highly compressed gas, compressible fluid, or supercritical fluid,comprising the steps of: providing pressure at or near supercriticalconditions in the flow stream at an outlet of said pump; positioning astatic orifice downstream of the pump outlet and between pressureregulators in said flow stream; controlling flow in the flow stream bycontrolling a pressure drop across a static orifice in the flow channel;and controlling a constant temperature of the flow stream, across thestatic orifice, as practicable to prevent degradation of saidcontrolling flow in the flow stream.
 13. The method of claim 12, whereinthe step of controlling flow comprises regulating a pump outlet pressurefrom a point upstream of the orifice and regulating back pressure from apoint downstream of the orifice.
 14. The method of claim 12, where thesteps of positioning a static orifice comprises regulating the forwardpressure of the flow stream at a point upstream of the restrictor with aforward-pressure regulator.
 15. The method of claim 12, wherein thepositioning further comprises controlling a pressure drop across thestatic orifice with a differential pressure transducer.
 16. The methodof claim 12, further comprising the steps of: combining said flowstream, at a point downstream of the pressure regulators, with a secondflow stream from a relatively incompressible fluid, wherein saidpositioning further comprises regulating a back pressure in the flowstream with a back pressure regulator at a point prior to said combiningsaid flow stream with said second flow stream.